Despite the growing number of genome-wide association studies (GWAS), genetic signals have rarely been traced to the causal genetic variant explaining the mechanistic basis of the observed association. This is particularly challenging for non-coding variants, which constitute 93% of top-scoring GWAS single-nucleotide variants (SNVs), given still incomplete regulatory annotations, and uncertainty of the relevant cell types, target genes, or upstream regulators. The challenge is even greater for complex traits such as obesity or disorders such as cancer and associated disorders, that involve multiple organs, hormonally- and neuronally-regulated signals, strong environmental effects, and pleiotropic interactions with other complex traits.
Obesity affects more than 500 million people worldwide and is one of the leading contributors to common and severe disorders, including type 2 diabetes, cardiovascular disorders, and cancer (Guh, D. P. et al., BMC Public Health 9, 88 (2009); Adams, K. F. et al. N Engl J Med 355, 763-778 (2006); Wang, Y., Adv Nutr 2, 23-31 (2011)). Thus, considerable efforts have been made to define its causal mechanisms, as understanding the genetic cause of obesity could illuminate the causal genetic mechanism of other disorders. For example, the fatso/fat mass and obesity associated (FTO) locus has been shown to possess the strongest association with obesity risk (Frayling, T. M. et al., Science 316: 889-894 (2007); Dina, C. et al., Nat Genet 39, 724-726 (2007); Tan, L. J. et al. PLoS One 9, e96149 (2014)). Despite considerable efforts to define causal mechanisms, the functional variant remains uncharacterized among 82 highly-associated SNVs, and the molecular and cellular intermediate phenotypes, mechanisms, and biological processes leading to obesity remain unknown.